tbuckley/cabot-search huggingface dataset:
LDE-paclitaxel in second or later lines in advanced pancreatic cancer: A phase I trial.
Authors: Bruna Bighetti, Raul Cavalcante Maranhão, Nora Manoukian Forones
Journal: Journal of Clinical Oncology (2023)

e16298 Background: Nanoparticles have been studied in association with chemotherapy, with objective of increasing the concentration of the drug in neoplastic cells and, thus, increasing its antitumor action. Nab-paclitaxel is a well-known nanotechnology association between paclitaxel and albumin and can be used in the treatment of advanced pancreatic cancer. LDE-Paclitaxel is a combination of paclitaxel and a synthetic molecule of low-density lipoprotein (LDE). It was previously evaluated in patients with gynaecological malignancies undergoing third-line treatment and showed higher rates of disease control than conventional regimens described in the literature. Our objective was to evaluate the efficacy of LDE-paclitaxel in the treatment of advanced pancreatic cancer (stage III and IV) in second or third line of therapy. Methods: This was a prospective phase I/II, single-arm study, in which we delivered LDE-Paclitaxel at a weekly dose of 85mg/m² to patients with pancreatic adenocarcinoma in second or third-line. The patients must had been through treatment of at least one standard chemotherapy scheme. Results: From October 2020 to November 2021, nine patients with advanced pancreatic adenocarcinoma were enrolled in this prospective, single-arm, phase 1/2 study in which we offered LDE-Paclitaxel at a dose of 85mg/m² intravenously, after progression to gemcitabine. During this period, patients underwent a maximum of 5 cycles, with no need to reduce the medication dose in any of the cycles, for any of the patients. LDE-paclitaxel presented mostly grade 1 and 2 toxicities, mainly anaemia and neuropathy; Grade 3 toxicity was presented by only 1 patient, which was acute kidney injury. Median overall patient survival was 20.14 months, and patient survival after enrolment in the study and initiation of LDE-paclitaxel use was close to 5 months, with no decline in the assessed quality of life indices. Conclusions: LDE-paclitaxel appears to be more tolerable, viable and less toxic than other standard chemotherapy in this setting. Our results suggest that LDE-paclitaxel could be a therapeutic possibility for patients with metastatic pancreatic cancer. For a better evaluation, further studies would be necessary, to obtain more data on the use of this medication in clinical practice and for a better understanding of other important outcomes. Clinical trial information: 4237198 .
A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer.
Authors: Jing Li, Zhi-yao You, Miao-fang Wu, Zhong-qiu Lin, Qing Chen
Journal: Journal of Clinical Oncology (2023)

e17532 Background: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this single-center Phase I trial, time-to-event Bayesian Optimal Interval Design (TITE-BOIN) was used. The starting dose for docetaxel was 60 mg/m 2 , with escalation in 5 mg/m 2 increments until the MTD was determined or the maximum dose level of 75 mg/m 2 was reached. The target dose-limiting toxicity (DLT) rate was 25%, and the total sample size was 30 patients. HIPEC was delivered immediately following the debulking surgery using the closed technique with a target temperature of 43 ℃ for 90 minutes. Results: A total of 30 patients were enrolled from August 2022 to November 2022. Among patients who received a docetaxel dose level ≤ 65 mg/m 2 , no DLT was reported. DLTs were observed in one patient at 70mg/m 2 docetaxel (grade 3 anemia) and three patients at 75mg/m 2 docetaxel (one grade 3 anemia, one grade 3 hepatic impairment and one grade 4 thrombocytopenia). When patients were treated with docetaxel at a dose of 75 mg/m 2 in combination with 75 mg/m 2 cisplatin, the estimated DLT rate was 25% which was closest to the target DLT rate and therefore selected as the MTD. Conclusions: For ovarian cancer patients who receive HIPEC following debulking surgery, docetaxel, in combination with a fixed dose of cisplatin (75 mg/m 2 ), can be safely used at intraperitoneal doses of 75 mg/m 2 (ClinicalTrials.gov identifier, NCT05410483).
The clinical value of homologous recombination deficiency score in prostate cancer.
Authors: Yan Wang, Min Qu, Zhenyang Dong, Qing Hao, Guomin Lin, Jinyi Song, Xu Gao
Journal: Journal of Clinical Oncology (2023)

e17011 Background: Aberrations in homologous recombination repair (HRR) genes serve as biomarkers for guiding the treatment decision of PARP inhibitors in prostate cancer (PCa). Homologous recombination deficiency (HRD) score which directly shows the consequence of the loss of HRR function (genomic scars) may be a more reliable biomarker for identifying patients who are sensitive to PARP inhibitors. Methods: This study involved 50 patients with PCa, including mHSPC (n = 37), mCRPC (n = 11), and locally advanced PCa (n = 2). Tumor tissue specimens were collected for targeted next-generation sequencing for 406 cancer-related genes and HRD detection. HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. All the experiments were performed in OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: The median HRD score was 34.5 (ranged from 14 to 64). With the median value as cutoff, the mutation rates of HRR were 32% (8/25) and 12% (3/25) in the high and low HRD score groups, respectively. BRCA2 mutations (P = 0.011), AR mutations (P = 0.032), RB1 mutations (P = 0.035) and altered HRR pathway (P = 0.017) were associated with high HRD scores. The mutation frequencies of AR and TP53 were significantly higher in mCRPC compared to mHSPC ( AR: 45.5% [5/11] vs 2.7% [1/37], P &lt; 0.001; TP53: 63.6% [7/11] vs 24.3% [9/37], P = 0.027). A total of 9 patients carried HRR germline mutations (5 BRCA2, 1 BRIP1, 1 RAD50, 1 RAD51D, and 1 ATM). It was found that patients with BRCA2 germline mutations had a higher HRD score (median = 37) than those with other germline mutations ( BRIP1: 25, RAD50: 19, RAD51D: 35, ATM: 36). In the 6 patients who received HRD-related treatments (including cisplatin based chemotherapy or olaparib), 1 of the 2 patients with low HRD score had PSA progression after 251 days (the other one was lost to follow up), while no PSA progression was observed in the 4 patients with high HRD score with a median follow-up of 107 days (range: 40-274 days). A mCRPC case with high HRD score (37) and HRR wild-type who received second line docetaxel+cisplatin even achieved undetectable PSA. Another mHSPC patient with a high HRD score (37) and a BRCA2 germline mutation also had no detectable PSA after first-line docetaxel+cisplatin therapy. Conclusions: To our knowledge, this is the first study in China reporting the association of HRD score and platinum-based treatments in PCa. Our results supported the possibility that HRD score could be predictive for the efficacy of platinum-based chemotherapy.
Efficacy and safety of induction chemotherapy with docetaxel + cisplatin in selected groups of patients with HNSCC.
Authors: Svetlana Kutukova, Julia V. Ivaskova, Natalia P. Belyak, Anna Varankina, Alexandra Androsova, Alexandra Razumova
Journal: Journal of Clinical Oncology (2023)

e18059 Background: We investigated the efficacy and safety of docetaxel + cisplatin (DC) induction chemotherapy vs TPF in patients with locally advanced HNSCC. Methods: Under our observation there were 22 patients in HNSCC (63,6% men and 36,4% women, aged 43 to 74 years (58.7±9.4 (95% CI 55.0-62.4)). The control group consisted of 18 patients (72,2% men and 27,8% women, aged 43 to 73 years (53.9±8.8 (95% CI 49.6-58.3). Both groups were comparable in terms of location, stage (III-IVA) and tumor differentiation. The patients of group 1 received DC (docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 ; q3w) as induction chemotherapy (ICT), while patients in the control group received TPF. Results: The planned number of ICT cycles (No. 3) in group 1 was received by 100% pts. and in the control group - 77.78% pts. (p = 0.02). At the control assessment according to RECIST 1.1, PR was registered in 77.3% pts. of group 1 vs 55.5% pts. in control group (p = 0.14), SD - in 22.7% vs 33.3: (p = 0.45), PD was registered only in patients of the control group - in 11.2% (p = 0.11). The frequency of registration of AEs: diarrhea gr.1-3 - 9.1% pts. group 1 vs 33.3% of pts. the control group (p = 0.06), nausea gr.1 -2 - 9.1% vs 22.2% (p= 0.25), asthenia gr. 1-2 - 4.5% versus 16.7% (p = 0.20), anemia gr. 1-2 - 9.1% vs. 16.7% (p = 0.47), neutropenia gr. 3-4– 4.5% versus 16.7% (p = 0.20). Reduction of doses of cytostatic up to 50% was performed in 4.5% pts. in group 1 and 16.7% pts. in the control group (p = 0.20). Conclusions: Induction chemotherapy in DC mode may be an effective and safe regimen in certain groups of patients with HNCH (for example, in patients with contraindications to 5-FU infusions, as well as in patients with high-risk HHNH for alternative surgical treatment or concurrent CRT as initial treatment of localized and locally advanced HNSCC.
Phase 2 study of bintrafusp alfa in recurrent/metastatic olfactory neuroblastoma.
Authors: Dara Mark Bracken-Clarke, Nyall R London, Marissa Mallek, Lisa M. Cordes, Seth M. Steinberg, Jenn Marte, Julius Strauss, Jason M. Redman, Danielle M. Pastor, Jeffrey Schlom, James L. Gulley, Charalampos S. Floudas
Journal: Journal of Clinical Oncology (2023)

TPS6116 Background: Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a rare malignant tumor of the nasal cavity, believed to arise from the basal cells of the olfactory neurosensory epithelium. ONB is often locally advanced at diagnosis with high rates of spread both locoregionally and systemically. Current therapy for locoregional disease is local resection with adjuvant (chemo-) radiotherapy. Actionable mutations are rare, and treatment options for recurrent or advanced, non-resectable, disease are limited and include off-label combination chemotherapy (most frequently platinum-containing) and somatostatin-directed therapies (ONB expresses somatostatin receptors). These are based on limited data, with response rates poorly characterized. Bintrafusp alfa is a first-in-class, bifunctional TGF-β “trap”/anti-PD-L1 fusion protein. Analysis of ONB has demonstrated both PD-1/PD-L1 (London et al, 2018) and TGF-β ligand expression (Romani et al, 2021). Pre-clinical and clinical data in advanced solid tumors demonstrate enhanced antitumor activity with combination PD-L1/TGF-β blockade, with responses observed independently of high PD-L1 levels (Strauss et al, 2020). Thus, combination PD-L1/TGF-β blockade in ONB is a rational approach in a setting of unmet clinical need. Methods: This study is a Phase 2 single-site, single-arm clinical trial of bintrafusp alfa (1200mg IV every 2 weeks for up to 26 doses) for patients with recurrent or metastatic ONB. Participants must co-enroll to the ONB Natural History study at the NCI (NCT4755205). Patients must not be candidates for local therapy, have received at least 1 line of systemic therapy (including a platinum salt), have RECIST 1.1 measurable disease and have adequate organ function. Prior checkpoint inhibitor therapy is permitted with patients cohorted according to checkpoint exposure; up to 21 checkpoint-naïve and 8 checkpoint-resistant patients will be enrolled. The primary objective is objective response rate by RECIST 1.1 with secondary endpoints including safety and tolerability, duration of response and overall survival; exploratory endpoints include pharmacokinetic analyses, PD-L1 and immune cell correlative analyses. The trial follows a Simon two-stage design, requiring ≥1 response in the first 12 patients. Tumor biopsy at enrollment is optional. Imaging for response assessment is planned for 8-week intervals and PET scan (preferably 68 Ga-DOTATATE) will be obtained for all patients at baseline and first restaging, then on an individualized basis per radiology advice. This study is presently open at the NCI with 5 patients enrolled as of January 2023. Clinical trial registry:NCT05012098. Clinical trial information: NCT05012098 .
Racial disparity in dose intensity of early-stage breast cancer chemotherapy.
Authors: Margaret Q. Rosenzweig, Susan R Mazanec, Adam Brufsky, Brittaney-Belle Elizabeth Gordon
Journal: Journal of Clinical Oncology (2023)

6556 Background: There are persistent, entrenched racial disparities noted in breast cancer outcomes. A basis for these disparities can be racial inequality for stage matched Black vs. White women in receiving early-stage breast cancer (ESBC) chemotherapy dose intensity of, at minimum, 85% or more of chemotherapy (historic gold standard) within prescribed timeframe. Our study measured dose reductions, early terminations, and overall dose intensity of ESBC chemotherapy in urban breast cancer centers and compared by race. Methods: Using a longitudinal, comparative descriptive design, treatment characteristics were measured in women receiving ESBC cancer chemotherapy in seven cancer centers in Western PA and Eastern Ohio. Dosing scheduled was calculated per patient chemotherapy prescription. Actual dose was measured as percentage of chemotherapy received / prescribed in “prescribed time,” meaning exact, ideal time to complete chemotherapy calculated from dose initiated without delay, dose reduction or early stoppage. The second measurement, “in any time,” measured chemotherapy completed over any course of time, incorporating delays and reductions. Results were dichotomized according to 85% of prescribed dose for both outcomes and compared by patient self-reported race (Black or White). Results: This study was conducted from August 2017 through June 2022. N=260 patients, race self-reported as 100 Black (38.5%) and 160 White (61.5%). Overall, n=36 (13.8%) had early termination of therapy. Early termination was more common for Black patients, 21%, vs 10% for White patients (p=.04). N=100 (38.3%) of all patients had some dose reduction, racially divided by 46.4% of Black patients vs. 34.3% of White patients, NS. By projected endpoint, Black patients received 77% (SD 24.1) of prescribed chemotherapy; White patients 86.7% (SD 16.6), p=.001. By “in any time” endpoint, Black patients received 86.5%, (SD 22.8) of prescribed therapy, White patients received 93.5% (SD 13.2), p=.002. By “in any time” measurement, 15% of White patients and 25% of Black patients did not receive the gold standard of 85% of prescribed chemotherapy. N= 7 of delays or terminations were due to disease progression, or poor response, and rarely, (n=4) to patient nonadherence. Largely, delays and early cessation were due to chemotherapy toxicity. Conclusions: Racial disparities in dose intensity and alterations of prescribed ESBC chemotherapy must be eliminated. Further examining the racial differences around dose delays and early chemotherapy termination, including racial barriers to patient- clinician communication around chemotherapy related toxicity, is essential to ensure equitable ESBC care and outcomes.
The spectrum of homologous recombination deficiency in cervical cancer: Is it also a cervical issue?
Authors: Muhammad Danyal Ahsan, Emily M. Webster, Ryan M Kahn, Sarah R. Levi, Murtaza Qazi, Luiza Perez, Jesse T. Brewer, Laura Keenahan, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Melissa Kristen Frey
Journal: Journal of Clinical Oncology (2023)

5543 Background: Tumors deficient in homologous recombination DNA damage repair (HR-DDR) demonstrate sensitivity to therapeutic agents targeting the HR-DDR pathway, such as poly-ADP ribose phosphate (PARP) inhibitors. The landscape of homologous recombination deficiency (HRD) is not well-characterized for cervical cancer; thus, we sought to analyze the prevalence of somatic pathogenic gene variants (PGVs) in HRD genes in cervical cancers. Methods: The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 was queried for all cervical cancer tumors via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of multiple tumors. PGV frequencies of 27 genes involved in HR-DDR were descriptively reported for cervical cancer tumors, with histologic stratification: ATM, ARID1A, ATRX, BRCA1, BRCA2, BARD1, BRIP1, BLM, BAP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Results: A total of 857 cervical tumors from 817 patients were included for analysis. At least one somatic PGV in an HRD gene was found in 16.5% of all tumors (141/857). When stratified by histological subtypes with at least 25 tumors sequenced, highest frequencies of ≥1 PGV in HRD genes were observed in mucinous cervical cancer (13/66, 19.7%), cervical adenocarcinoma (48/262, 18.3%), squamous cell cervical cancer (53/349, 15.2%), adenosquamous cervical cancer (6/43, 14.0%) and neuroendocrine cervical cancers (5/42, 11.9%). Substantial rates of PGVs in HRD genes were also observed in histological subtypes with fewer than 25 sequenced tumors. Across all tumors, HRD genes with the highest frequencies of PGVs were ARID1A (9%), BAP1 (3%), ATM (1.6%) and BRCA1 (1.6%). Conclusions: NGS data demonstrate a substantial rate of somatic PGVs in HRD genes in cervical cancers, including among HPV related subtypes. These data suggest the need to expand routine functional HRD status assessment to cervical cancers in order to further characterize the landscape of HRD in these tumors. Furthermore, genetically driven clinical trials are warranted to evaluate the efficacy of HRD-targeted therapies such as PARP inhibitors, ataxia telangiectasia, and Rad-3 related kinase (ATR) inhibitors. [Table: see text]
Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.
Authors: Mingwei Li, Jiayue Qin, Xiayuan Liang, Tao Zhou, Yanrui Zhang, Huina Wang, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e16551 Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.
CD73/adenosine pathway-related gene signature for intratumor heterogeneity and immune infiltration in prognosis of lung adenocarcinoma.
Authors: Wang Luo, Shuhua Zhang
Journal: Journal of Clinical Oncology (2023)

e20524 Background: Adenosine is an immunosuppressive molecule that can inhibit the activity of immune cells, particularly T cells, and promote tumor growth. CD73, also known as ecto-5'-nucleotidase, is a cell-surface enzyme that plays a role in the adenosine pathway can catalyzes the conversion of AMP to adenosine. Establish and evaluate a prognosis model based on CD73/ Adenosine pathway will help to understanding of the biological mechanisms in lung adenocarcinoma (LUAD) and providing more accurate predictions for patients' treatment. Methods: The RNA sequencing (RNA-seq), whole exome sequencing (WES) and clinical data were obtained from LUAD cohorts of the Cancer Genome Atlas (TCGA). CD73/ Adenosine pathway-related genes were identified by screening for genes that were in both the CD73 STRING network (confidence = 0.9, 1st shell ≤50 interactors) and the KEGG purine metabolism pathway gene list(map00230). Least absolute shrinkage and selection operator (LASSO) regression was conducted to develop a CD73/ Adenosine pathway-related risk score (CD73RS). Time-dependent ROC curve and survival analysis were conducted in LUAD-TCGA cohort to verify the predictive performance of CD73RS. The MATH (Mutant-Allele Tumor Heterogeneity) ITH scores were calculated to evaluate intratumor heterogeneity (ITH) in LUAD-TCGA WES "maf" files using the R package "maftools" and the "math.score" function. TIMER 2.0 database(http://timer.cistrome.org/) was conducted to estimation of tumor microenvironment to further understand the molecular features of CD73RS. An independent cohort (GSE72094) was used to verify the prognostic effect of CD73RS. Results: A prognosis prediction model based on 21 CD73/ Adenosine pathway-related genes was established using LASSO regression. Kaplan-Meier survival analysis of the risk model from LUAD-TCGA cohort showed that the high-risk group had a significantly worse prognosis (HR = 3.298, P = 1.26e-08). The area under the curve (AUC) in time-dependent ROC curve at 1, 3 and 5 years were turn out to be 0.794, 0.722 and 0.686, respectively. The validation set also showed worse prognosis in high-risk group(HR = 1.473,p = 0.0403). In the high-risk group, there was a higher ITH score compared to the low-risk group (p = 0.0094), along with lower infiltration levels of B cells(p = 7.23e-15), CD4+ T cells(p = 0.003), macrophage cells(p = 0.016), and myeloid dendritic cells(p = 0.037). Conclusions: We established and validated a CD73/ Adenosine pathway risk model that exhibits a robust predictive performance for the outcome of patients with LUAD. The CD73/Adenosine pathway has been shown to play a role in both self-driven genomic changes, such as intra-tumor heterogeneity (ITH), as well as non-autonomous processes, such as immune microenvironment adaptation, which contribute to tumor plasticity and development.